Discovery of potent STAT3 inhibitors using structure-based virtual screening, molecular dynamic simulation, and biological evaluation

Weifeng Liu; Zhijie Chu; Cheng Yang; Tianbao Yang; Yanhui Yang; Haigang Wu; Junjun Sun

doi:10.3389/fonc.2023.1287797

Discovery of potent STAT3 inhibitors using structure-based virtual screening, molecular dynamic simulation, and biological evaluation

Front Oncol. 2023 Nov 2:13:1287797. doi: 10.3389/fonc.2023.1287797. eCollection 2023.

Authors

Weifeng Liu¹, Zhijie Chu¹, Cheng Yang¹, Tianbao Yang¹, Yanhui Yang², Haigang Wu³, Junjun Sun¹

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China.
² Department of Emergency Trauma Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, China.
³ School of Life Sciences, Henan University, Kaifeng, Henan, China.

Abstract

Introduction: Signal transducer and activator of transcription 3 (STAT3) is ubiquitously hyper-activated in numerous cancers, rendering it an appealing target for therapeutic intervention.

Methods and results: In this study, using structure-based virtual screening complemented by molecular dynamics simulations, we identified ten potential STAT3 inhibitors. The simulations pinpointed compounds 8, 9, and 10 as forming distinct hydrogen bonds with the SH2 domain of STAT3. In vitro cytotoxicity assays highlighted compound 4 as a potent inhibitor of gastric cancer cell proliferation across MGC803, KATO III, and NCI-N87 cell lines. Further cellular assays substantiated the ability of compound 4 to attenuate IL-6-mediated STAT3 phosphorylation at Tyr475. Additionally, oxygen consumption rate assays corroborated compound 4's deleterious effects on mitochondrial function.

Discussion: Collectively, our findings position compound 4 as a promising lead candidate warranting further exploration in the development of anti-gastric cancer therapeutics.

Keywords: STAT3; gastric cancer; molecular docking; molecular dynamic simulation; structure-based virtual screening.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work is supported by Henan province development breakthrough program (202102310110).